IFITM3 promotes bone metastasis of prostate cancer cells by mediating activation of the TGF-\u03b2 signaling pathway

Xi Liu,Yi Gao,Fajun Qu,Yao Li,Xiaoqun Yang,Danfeng Xu,Xiuwu Pan,Yinghui Fan,Lu Chen,Xingang Cui,Jianmin Lv,Yi Hong,Jianlei Lu

doi:10.1038/s41419-019-1750-7

Abstract

Advanced-stage prostate cancer (PCa) is often diagnosed with bone metastasis, for which there are limited therapies. Transforming growth factor β (TGF-β) is known to induce epithelial–mesenchymal transition (EMT), and abundance of TGF-β in the bone matrix is one of the important growth factors contributing to bone metastasis. TGF-β is reported as a key mediator of bone metastasis, but the underlying mechanism has not been elucidated. It was found in our study that Interferon-inducible Transmembrane Protein 3 (IFITM3) played a key role in the regulation of malignant tumor cell proliferation, invasion, and bone migration by binding to Smad4, thus activating the TGF-β-Smads Signaling Pathway. Lentivirus-mediated short hairpin RNA (shRNA) knockdown of IFITM3 inhibited cell proliferation and colony formation, induced apoptosis and inhibited migration by reversing EMT and downregulating the expression of metastasis-related molecules including FGFs and PTHrP. Microarray analysis showed that IFITM3 knockdown could alter the MAPK pathway associated with TGF-β-Smads signaling. By knocking down and overexpressing IFITM3, we demonstrated that IFITM3 expression level had an effect on MAPK pathway activation, and this change was more pronounced upon exogenous TGF-β stimulation. These results suggest that IFITM3 played an oncogenic role in PCa progression and bone metastasis via a novel TGF-β-Smads-MAPK pathway.

Highlights

Prostate cancer (PCa) remains one of the most universal malignant tumors and the major cause of cancer-associated death in the male worldwide[1]
By examining the key molecules of common pathways such as cell cycle, proliferation using the Western blotting method, we found that P38-MAPK activation was significantly weakened and the expression level of cell cyclerelated proteins CDK1 and CDC2 was decreased, suggesting that Interferon-inducible Transmembrane Protein 3 (IFITM3) may affect the proliferation of PCa cells through regulating cell cycle mediated by MAPK pathway
We found that the E-Cadherin and N-Cadherin changed after silence IFITM3, knowing that E-cadherin loss in epithelial cell adhesion is a characteristic feature of epithelial–mesenchymal transition (EMT), which allows to enhance cells movement and aggressiveness by disrupting cell-cell contacts[22]

Summary

Introduction

Prostate cancer (PCa) remains one of the most universal malignant tumors and the major cause of cancer-associated death in the male worldwide[1]. About 90% cancerrelated deaths were attributed to metastasis. The bone is the most common site of PCa metastasis[2]. About 70% of advanced PCa patients were diagnosed with bone metastases. PCa, with breast cancer (BCa) together, takes up over 80% cases of bone metastatic disease[3].

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Results

Conclusion